The RAS-MAP kinase signaling cascade is a key pathway that is activated in the vast majority of human pancreatic cancers. Among the multiple protein players critical to its biological output, the downstream kinase MEK, has emerged as an attractive candidate for pharmacologic inhibition. With the availability of a number of recently developed MEK specific agents, efforts need to be directed toward the design of a clinical trial wherein dosing and schedule have been optimized. The primary goal of this proposal is to systematically investigate MEK inhibition as a strategy for the treatment of pancreatic cancer using a novel imaging approach in preclinical models that have historically been difficult to study. A genetically engineered mouse model of pancreatic ductal adenocarcinoma will be modified by the introduction of reporters for MEK activity and for induction of apoptosis. Cre-dependent induction of these onboard molecular imaging reporters will enable bioluminescence imaging-based monitoring of tumor burden, targeted inhibition of MEK, and longitudinal treatment response in live animals as imaged by apoptosis induction. We hypothesize that MEK inhibitors will offer clear therapeutic benefit when integrated into currently adopted chemo- and radiotherapy regimens for the treatment of pancreatic cancer. However, the current paradigm involving chronic daily dosing that has become standard practice in drug clinical trials today will be evaluated here. Our molecular imaging approach will increase our understanding of the relationship between dynamics of target modulation and therapeutic outcome. Multiple doses and schedules will be evaluated to optimize treatment by comparing sustained versus maximal target inhibition. We believe this to be the first study undertaken to optimize MEK inhibitor treatment on the basis of bioluminescent imaging of pancreatic cancer originating and proliferating directly in the mouse pancreas. Additionally, a panel of primary orthotopic xenografts will be tested that will more likely reflect the heterogeneity encountered in clinical trials. The promise of diffusion-MRI as a surrogate biomarker of early therapeutic response will also be explored for future clinical translation. The use of novel imaging surrogates for key signaling events could have a major impact on the treatment of pancreatic cancer, facilitating an early assessment of patient response as well as accelerating trial timelines. We propose a paradigm shifting strategy for the rational design and optimization of clinical trials by integratig novel mouse models with imaging readouts of drug-target interaction. The net impact will provide for improved therapeutic outcomes in pancreatic cancer and serve as a prototype approach applicable to other targets and patient populations. PUBLIC HEALTH RELEVANCE: There is an urgent need to develop more effective therapies to improve the low survival rate for pancreatic cancer. Rationally designed MEK inhibitor-based therapies have the potential to improve the efficacy of current standard of care (gemcitabine/radiation) for this disease. This project will provide unique molecular imaging capabilities to optimize MEK inhibitor-based combination therapies in human pancreatic cancer and guide future clinical trial design with this mechanistic class of agents.